Background: According to the World Health Organization, social isolation, particularly of older adults, is a public health issue endangering the well-being of individuals, families, and communities. Social isolation affects health through biological, behavioral, and psychological pathways and is associated with physical and psychological/emotional well-being, increases morbidity and mortality rates, and lowers quality of life. Purpose: This systematic review examined the relationship between social isolation and physical health, including subjective and objective dimensions, and factors that influence this relationship in adults. Methods: This systematic review examined six electronic databases covering the field of health and human services and included results from 1 January 2017 to 10 March 2023 with key terms including adult social connection or social isolation coupled with health, physical, psychological, emotional, mental, or behavioral. The initial search yielded 925 research articles across all databases and was narrowed to 710 when the decision was made to focus on social isolation and physical health. Covidence was used throughout the retrieval and appraisal process, as provided in a PRISMA flow diagram. Twenty-four studies that scored 90 or above in the appraisal process were included in the systematic review. Results: The studies represented included seven studies conducted in the United States and seventeen studies conducted internationally. Regarding study design, twenty-three studies were quantitative, one was qualitative, and one was mixed methods. The majority of quantitative studies were correlational in design with nine being longitudinal. The majority of studies were based on large national data sets representing in total 298,653 participants aged 50 and older. The results indicate that social isolation is related to increases in inflammatory biomarkers associated with diseases, all-cause mortality, lower expectations of longevity, and frailty. In addition, social isolation was associated with cognitive decline and disruptions in sleep. Poor oral health increased social isolation. The results further indicated that decreased physical performance/function and a decline in physical activity were associated with social isolation, as well as decreased overall physical health, poor health behaviors, and self-care, and decreased health-related quality of life. Further research is warranted to examine the possible bidirectionality of these relationships and possible mediating, moderating, or confounding variables. Implications: Future research is needed to explore the biological and behavioral pathways in which social isolation negatively impacts physical health. Going forward, studies are needed that move beyond descriptive, exploratory methods and integrate data from qualitative and mixed-method designs that will inform the development and testing of a conceptual framework related to social isolation and health. By advancing the science behind social isolation, comprehensive interventions can be identified and tested with implications at the individual, family, community, and societal levels to reduce social isolation, particularly among adults, and improve health and quality of life.